Use of natural EGFR inhibitors to prevent dermatitis, such as due to cleansers

ABSTRACT

People&#39;s hands undergo daily exposure to hot, cold, and chemicals (such as cleansers). These exposures can cause dermatitis due to activation of the Epidermal Growth Factor Receptor (EGFR). One effect of activation of the EGFR is hyperproliferation of skin cells, which presents as rough, dry, and/or peeling hands, generally known as dermatitis. The use of a natural EGFR inhibitor, such as genistein or quercetin, can help to treat or prevent these kinds of dermatitis.

PRIOR APPLICATIONS

[0001] This application is a divisional of application Ser. No.10/085,978, filed Feb. 27, 2002, which is on prior provisionalapplication No. 60/271,894, filed Feb. 27, 2001, the disclosures ofwhich are both incorporated herein by reference.

BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] This invention relates to the use of EGF receptor inhibitors,especially those occuring naturally in produce, foodstuffs, and thelike, such as the isoflavinoid genistein, for preventing unwanted sideeffects when retinoids are used topically for treating humans.

[0004] 2. The State of the Art

[0005] Topical retinoid administration has been used to treat a widevariety of dermatological ailments. For example, acne vulgaris has beentreated with all-trans retinoic acid (tretinoin), sold under thewell-known brand name Retin-A (from Janssen Pharmaceuticals), and thelesser known brand name Avita (from Penederm); oral 13-cis retinoic acid(isotretinoin; sold under the brand name Accutane for oraladministration) has been used for severe cases of acne. 9-cis retinoicacid (alitretinoin) has been used topically to treat cutaneous lesionsof AIDS-related Kaposi's sarcoma (Panretin brand gel, from LigandPharmaceuticals), and systemically to treat chronic eczema and renalcancer. Synthetic retinoids that have been approved for use against acneand psoriasis include adapalene (sold under the brand Differin) andtazarotene (sold under the brand name Tazorac), respectively. Psoriasisalso has been treated with the trimethylmethoxyphenyl analogue ofretinoic acid ethyl ester (etretinate; sold under the brand namesSoriatane (acetretin), and formerly Tegison (etretinate)). Retinoidshave also been used for treating other kinds of acne (such as cysticacne and acne rosacea) and various keratinization disorders (such as,ichthyoses (such as lamellar ichthyosis, ichthyosis vulgaris),pityriasis rubra pilaris, and Darier's disease). Retinoids have alsobeen used for skin cancer and chemotheraphy of precancerous lesions andchemoprophylaxis (such as for basal cell and squamous cell carcinomasand keratoacanthoma). Retinoids have also been used for treating suchskin conditions as warts, hyperkaratotic eczema of the hands and feet,and cutaneous sarcoidosis. In addition, retinoids have been used fortreating photoaged skin, with compositions such as sold under the brandname Renova. Thus, retinoids are widely used both topically andsystemically (orally) for a wide variety of conditions.

[0006] The present inventors and those working with them have inventedother uses for retinoids, including preventing photoaging of human skin(e.g., U.S. Pat. No. 5,837,224, U.S. Pat. No. 6,130,254, and applicationnumber 615218, filed Jul. 13, 2000), preventing and reversingchronological aging of human skin (e.g., application number 28,435,filed Feb. 24, 1998), treating post-inflammatory hyperpigmentation inblack skin (e.g., U.S. Pat. No. 5,750,570 and U.S. Pat. No. 6,017,960),preventing UV-induced loss of collagen biosynthesis (e.g., applicationnumber 285,860, filed Apr. 2, 1999), prevention of UV-induced functionalvitamin A deficiency (e.g., application number 418,413, filed Oct. 14,1999), preventing scarring and inflammation due to acne (e.g., 576,597,filed May 22, 2000). The disclosures of these patents and applicationsare incorporated herein by reference.

[0007] While those trained in the use of retinoids are cognizant oftoxicity issues, much more common and predictable are common sideeffects, such as erythema (redness), scaling, burning, and/or pruritus(itching), especially when retinoids are used long term. E.g., J W Fluhret al., “Tolerance profile of retinol, retinaldehyde and retinoic acidunder maximized and long-term clinical conditions”, Dermatology 1999;199 Suppl 1:57-60.

[0008] Protein tyrosine kinases are involved in regulating criticalfunctions in mammalian cells (e.g., cell growth, cell death,inflammation, and so on). There are two classes of protein tyrosinekinases: receptor protein tyrosine kinases and nonreceptor proteintyrosine kinases. Many growth factor receptors on cell surfaces haveintrinsic protein tyrosine kinase activity (i.e., the receptor proteinkinases), so that when the growth factor binds to its receptor on thecell surface, it stimulates the intracellular protein tyrosine kinaseactivity. This intrinsic activation initiates a signal transductioncascade that typically results in cell growth and survival (e.g.,effects expected from growth factors).

[0009] EGFR (Epidermal Growth Factor Receptor) is a transmembraneprotein that includes a bound protein tyrosine kinase (PTK) in theintracellular or cytoplasmic portion, and hence the EGFR has “intrinsic”protein tyrosine kinase activity. After EGF binds to the extracellularportion of the EGFR, the intracellular portion having the PTK moiety canbe activated by phosphorylation with ATP (adenosine triphosphate),releasing ADP in the process. When the PTK enzyme portion of the EGFR isactivated, it acts on its substrate, which is another EGFR (if one isnearby). (Depending on the particular receptor, there may be a fewreceptors or there may be thousands of receptors in a given cell'smembrane.) The activated EGFR activates an adjacent EGFR byphosphorylating its cytoplasmic portion (which contains the bound PTK)with the ATP. The phosphorylated EGFR (EGF-R-{circle over (P)}) with theactive PTK enzyme catalyzes various reactions that result in nuclearsignalling, up-regulating or down-regulating various genes, withconcommitant effects on the cell. While this activation is occurring,the first EGFR bound to the EGF may then bind to another ATP andactivate the cytoplasmic portion of yet another EGFR, increasing thenuclear signalling. Thus, as EGFRs are activated, they can activateother EGFRs so that the entire signal is amplified.

[0010] In one mode of action, it is known that retinoids cause anelevation in the heparin-binding epidermal growth factor (HB-EGF; onemember of the EGF family that binds the EGFR), which, through thenuclear signalling just discussed, causes hyperplasia and subsequentscaling and peeling of the skin, a side effect common to many who useretinoids topically. (E.g., J-H Xiao et al., “Identification ofheparin-binding EGF-like growth factor as a target in intercellularregulation of epidermal basal cell growth by suprabasal retinoic acidreceptors”, The EMBO J., Vol. 18, No. 6, pp. 1539-1548 (1999).) When apharmacological retinoid is applied topically to skin or taken orally,the EGFR (epidermal growth factor receptor) is activated by the releaseof HB-EGF. The EGFRs are located on cells in the epidermis, and theiractivation causes the cells in the lower epidermis to proliferateexcessively. The excessively proliferating cells cause upward pressureon the outward migrating cells, resulting in an excessive number ofcells arriving at the surface of the skin. This hyperproliferation ismanifest as peeling, scaling, and/or dryness of the skin. Retinoids haveother modes of action, but this mode is believed to be responsible formany of the side effects that deter patients from continued use ofretinoid therapy or decrease the benefit they receive (subjectivelytrading the discomfort of one problem for a lesser problem). Other thanterminating therapy, topically applied emollients, moisturizers,humectants, and the like are the typical adjuncts to topical retinoidtherapy for mitigating these detrimental side effects. In human skinorgan culture it was shown that synthetic EGFR tyrosine kinaseinhibitors blocked actions of HB-EGF induced by micromolarconcentrations of retinoic acid. (S. W. Stoll and J. T. Elder, “Retinoidregulation of heparin-binding EGF-like growth factor gene expression inhuman keratinocytes and skin”, Exp. Dermatol., 1998: 7:391-397.) Moreparticularly, it was shown that after exposure to a retinoid, the HB-EGFincreased, but the EGFR tyrosine kinase inhibitors prevented thisincrease from causing hyperplasia.

[0011] The medical arts have been focussing on the EGFR in connectionwith anticancer therapies because links have been shown between the EGFRsubfamily of tyrosine kinases and human cancers, including that varioustumors express EGFR. Thus, researchers have been looking towardstyrosine kinase inhibitors as anticancer agents because of the existenceof EGFR expression by tumor cells. F. Ciardiello, “Epidermal GrowthFactor Receptor Tyrosine Kinase Inhibitors as Anticancer Agents”, Drugs2000, 60 Suppl. 1, 25-32; and E. Raymond et al., “Epidermal GrowthFactor Receptor Tyrosine Kinase as a Target for Anticancer Therapy”, id.at 15-23 (the disclosures of which are incorporated herein byreference). These inhibitory compounds include an extremely wide varietyof molecules, including monoclonal antibodies, immunotoxin conjugates,ligand-toxin recombinant proteins, EGFR protein tyrosine kinaseinhibitors, and tyrosine kinase inhibitor-ligand conjugates. As theidentified cancers that express EGFR include lung, colorectal, advancedgastric, pancreatic, ovarian, breast, and prostate, administration ofthese compounds is by injection (system or direct acting) or orally.Additionally, more advanced synthetic compounds are more selective andmore potent than more naturally occuring compounds. The nuclearsignalling mediated by EGFRs can be decreased by inhibiting the bindingof EGF to the receptor, by inhibiting the binding of the EGF-EGFRcomplex to ATP, and/or by inhibiting the activation of the EGFRsubstrate by (EGF-R-{circle over (P)}).

[0012] Certain inhibitors of protein tyrosine kinase at lowerconcentrations inhibit other tyrosine kinases at higher concentrations.Among these are EGF-R inhibitors including AG-494 (a member of thetyrphostin family of tyrosine kinase inhibitors), AG-825(5-[(Benzthiazol-2-yl)thiomethyl]-4-hydroxy-3-methoxybenzylidenecyanoacetamide),AG-1478 (4-(3-Chloroanilino)-6,7-dimethoxyquinazoline) and4-aniloquinazoline derivatives (W. A. Denny, “The 4-anilinoquinazolineclass of inhibitors of the erbB family of receptor tyrosine kinases,”Farmaco 2001 January-February;56(1-2):51-6, discussing both reversiblyand irreversibly binding analogs), EI-146 (an Erbstatin analog),methyl-2,5-dihydroxycinnamate, HDBA(2-Hydroxy-5-(2,5-dihydroxybenzylamino)-2-hydroxybenzoic acid; Onoda etal., J. Natural Products, 52:1252,1989), Lavendustin A, RG-13022 (anon-phenolic tyrphostin analog which inhibits the EGFR), RG-14620 (anon-phenolic tyrphostin analog which is selective for the EGFR and longacting), Tyrphostin 23 (RG-50810), Tyrphostin 25([(3,4,5-trihydroxyphenyl)-methylene]-propanedinitrile, Gazit et al., J.Med. Chem., 32:2344, 1989; also known as RG-50875), Tyrphostin 46,Tyrphostin 47 (also known as RG-50864 and AG-213), Tyrphostin 51, andTyrphostin 1.

[0013] A review article by S. B. Noonberg and C. C. Benz (“TyrosineKinase inhibitors Targeted to the Epidermal Growth Factor ReceptorSubfamily—Role as Anticancer Agents”, Drugs, 2000 April:59(4) (thedisclosure of which is incorporated herein by reference)) describesvarious approaches for inhibiting the kinase activity of EGF receptors,including antibodies, immunotoxin conjugates, ligand-binding cytotoxicagents, and small molecule kinase inhibitors.

[0014] Small nucleotide inhibitors have also been developed forinhibiting EGFR, as well as for such kinases as JNK, MEKK, and othersthat activate EGFR signalling. Exemplary U.S. patents include U.S. Pat.Nos. 5,914,269 and 6,187,585 for EGFR inhibition, U.S. Pat. Nos.5,877,309, 6,133,246, and 6,221,850 for JNK inhibition, U.S. Pat. No.6,168,950 for MEKK inhibition, and other such as U.S. Pat. Nos.6,054,440, 6,159,697, and 6,262,241 (the dislcosures of which are allincorporated herein by reference). Most are disclosed as suitable fortransdermal administration to affect the local dermis, via reference totextbook methods for preparing topically-applied compositions, althoughno reason is given for such treatment (i.e., no dermal condition isidentified that might be treated by such therapy), nor is any efficacyshown for transdermal delivery (i.e., there is no evidence that smallnucleotide inhibitors can be applied

SUMMARY AND OBJECTS OF THE INVENTION

[0015] In light of the foregoing, it would be beneficial to prevent thepeeling, scaling, and dryness that accompanies topical and systemic(oral) retinoid therapy without significantly diminishing the desiredtherapeutic effect, whether by antagonism, competition, or otherwise. Itwould also be useful to provide this benefit without interfering with orcomplicating the retinoid treatment regimen, thereby maintaining if notimproving patient compliance with the retinoid therapy.

[0016] Towards this end, we have discovered that adminstration of one ormore compounds that inhibit EGFR signalling reduces the peeling,scaling, and dryness side effects of therapeutically-administeredretinoids. Preferably, these compounds include naturally occuringproducts, such as isoflavones, one example of which is genistein (whichis found in raw soy products), although synthetic analogs thereof arealso likely to be useful. The inhibitor may a reversible inhibitor, itmay irreversibly bind the receptor, or a combination thereof may beused. Preferably, the admistration of the EGFR inhibitor is topically.

[0017] Accordingly, this invention provides a method for diminishing theside effects of topical and systemic retinoid therapy through the use ofapplication of an EGFR inhibitor, preferably a natural product, andpreferably by topical administration. The administration can beconcurrent with the retinoid therapy, such as administering acomposition comprising both a retinoid and a natural EGFR inhibitor, itcan be administered as desired by the patient, such as with a separatecomposition comprising a natural EGFR inhibitor and applied as needed bythe patient, or it can be a combination of these methods.

[0018] In addition, in another embodiment this invention alleviates thesymptom of peeling due to hyperproliferation, regardless of the sourceof the proliferation (which can range from retinoid therapy to sunburn).

[0019] In other embodiments, this invention provides variouscompositions suitable for topical and systemic application to humanskin, including a composition comprising a retinoid and an EGFRinhibitor, preferably a composition comprising a combination of aretinoid and a natural EGFR inhibitor, as well as a topical compositioncomprising an EGFR inhibitor and an emollient, moisturizer, and/orhumectant.

[0020] In yet another embodiment, this invention provides a cleansercomposition, and a composition for ameliorating irritation and peelingdue to soaps and other compositions causing contact dermatitischaracterized by hyperproliferation. More specifically, in one aspectthis invention provides a cleanser, comprising a soap or surfactant andan EGFR inhibitor, more preferably an isoflavinoid such as genistein, ora ground or powdered botanical, such as soybeans which containgenistein. In another aspect, the invention provides a dispersion and/orsuspension of an EGFR inhibitor, more preferably an isoflavinoid such asgenistein, or a ground or powdered botanical, such as soybeans whichcontain genistein, in a form such as a lotion or cream, for treatingcontact dermatitis characterized by hyperproliferation.

BRIEF DESCRIPTION OF THE FIGURES

[0021]FIG. 1 depicts the ability of genistein to inhibit the activation(phosphorylation) of EGFR by UV radiation of human skin, depicted as thefold change in the amount of phosphorylated receptor, with an insertshowing a Western blot comparing the total EGFR with that which has beenactivated/phosphorylated (EGF-R-(E)).

DETAILED DESCRIPTION OF SPECIFIC EMBODIMENTS

[0022] Natural and synthetic retinoid analogs for topical or systemicadministration include vitamin A (retinol), vitamin A aldehyde(retinal), vitamin A acid (retinoic acid (RA)), including all-trans(tretinoin), 9-cis (alitretinoin), and 13-cis (isotretinoin) retinoicacids), etretinate (trimethylmethoxyphenyl analogue of retinoic acidethyl ester), and others as described in EP-A2-0 379367, U.S. Pat. No.4,887,805, and U.S. Pat. No. 4,888,342 (the disclosures of which are allincorporated herein by reference). Various synthetic retinoids andcompounds having retinoid activity, to the extent that they exhibitretinoid activity in vivo, are described in various patents assigned ontheir face to Allergan Inc., such as in the following U.S. Pat. Nos.5,514,825; 5,698,700; 5,696,162; 5,688,957; 5,677,451; 5,677,323;5,677,320; 5,675,033; 5,675,024; 5,672,710; 5,688,175; 5,663,367;5,663,357; 5,663,347; 5,648,514; 5,648,503; 5,618,943; 5,618,931;5,618,836; 5,605,915; 5,602,130. Still other compounds described ashaving retinoid activity are described in other U.S. Pat. Nos.5,648,563; 5,648,385; 5,618,839; 5,559,248; 5,616,712; 5,616,597;5,602,135; 5,599,819; 5,556,996; 5,534,516; 5,516,904; 5,498,755;5,470,999; 5,468,879; 5,455,265; 5,451,605; 5,343,173; 5,426,118;5,414,007; 5,407,937; 5,399,586; 5,399,561; 5,391,753; and the like, thedisclosures of all of the foregoing, and literature references, areincorporated herein by reference. There are also numerous experimentalretinoids compounds being developed and undergoing further refinement.

[0023] Our prior patents and application on photoaging of human skinteach that UV irradiation of human skin induces MMPs, enzymes thatdegrade collagen. Using the methodologies described therein, weinvestigated whether UV irradiation of human skin also inducesactivation of the EGFR, and whether genistein had any effect on thisactivation. Using human volunteers (each having given informed consentin writing), selected areas of skin (usually from the hip or buttocks)on each subject were treated with a standard vehicle or genistein (5%dissolved in the standard vehicle), occluded for 24 hours, and then twoof the sites, one for genistein and one for the vehicle, were irradiatedwith UV radiation equivalent to 2 MEDs. Each of the sites was biopsied acertain time after irradiation to determine the effect of genistein onthe parameter being examined. For determining the effect of genistein(if any) on EGFR activation/phosphorylation, the time between UVexposure and biopsy of both the irradiated and non-irradiated sites wasabout 30 minutes. Shown in FIG. 1 is an inset of a Western blotdepicting the total EGFR protein under the various conditions for asingle human volunteer, and the amount of phosphorylated (activated)receptor protein found under each of the various conditions for thatperson. The graph in FIG. 1 is a quantitative depiction of the results,the quantitation performed using Western blots from five individualvolunteers. As shown in the figure, neither the vehicle nor genisteinactivated/phosphorylated EGFR in the un-irradiated sites. However, thebiopsy of the irradiated sites showed that UV radiation does activateEGFR in human skin, and that genistein inhibits this activation. HenceUV radiation can be used as a substitute agonist instead of retinoids todetermine in vivo if a given compound applied topically will prevent theactivation of the EGFR. Of course, for in vivo testing the compound mustbe screened not only for human safety, but also, using this protocol, toassure it is not a UV sunscreen, whereby if EGFR activation after UVirradiation is inhibited, it is known that the inhibition was not due tosunscreen effects from the test compound.

[0024] Genistein is part of a group of naturally occuring flavones andisoflavones that also includes quercetin, equol, indolecarbazole,staurosporine, lavendustin, daidzein, and erbstatin that are useful inpracticing this invention. These compounds are not only relatively smallmolecules that can penetrate the skin when applied topically, they arealso part of a family of molecules that inhibit protein tyrosinekinases. Various small molecule inhibitors of receptor protein tyrosinekinases that may also be useful in this invention are described by D. H.Boschelli, “Small molecule inhibitors of receptor tyrosine kinases”,Drugs of the Future, 24(5), 515-537 (1999) (the disclosure of which isincorporated herein by reference). Receptor tyrosine kinase inhibitorscan be reversibly bound the to receptor or irreversibly bound. D. W.Fry, “Inhibition of the Epidermal Growth Factor Receptor Family ofTyrosine Kinases as an Approach to Cancer Chemotherapy: Progression fromReversible to Irreversible Inhibitors”, Pharmacol. Ther., Vol. 82, Nos.2-3, pp. 207-218 (1999); and D. W. Fry, “Site-directed irreversibleinhibitors of the erbB family of receptor tyrosine kinases as novelchemotherapeutic agents for cancer”, AntiCancer Drug Design (2000), 15,3-16 (the disclosures of which are incorporated herein by reference).Unlike the desire of those treating cancer, who select irreversibleinhibition, both reversible and irreversible inhibitors are useful forpracticing the present invention. Thus, many of the inhibitors mentionedabove, and in the publications mentioned above, are likely to be usefulin practicing this invention. Generally, inhibitor compounds that arelikely to pentrate the skin have a molecular weight of less than about1000 and are non-polar in nature, although present formulationtechniques, including the use of penetration enhancing compositions, canbring additional inhibitor compounds into the gambit of being useful forthis invention.

[0025] Genistein and its β-glucoside conjugate genistin, can be found insoy milk, tofu (bean curd), miso (bean paste), natto (fermentedsoybeans), and soy sauce. Other natural EGFR activation inhibitors, andderivatives thereof, include staurosporine, aeroplysinin (K. Hinterdinget al., “Synthesis and biological evaluation of aeroplysinin analogues:a new class of receptor tyrosine kinase inhibitors,” Bioorg Med Chem1998 August; 6(8):1153-62; H. Waldmann et al., “Selective Inhibition ofReceptor Tyrosine Kinases by Synthetic Analogues of Aeroplysinin,”Angew. Chem. Int. Ed. Engl. 1997, 36, No. 13-14, 1541-1542), lavendustinA (M. S. Symth et al., “Non-amine based analogues of lavendustin A asprotein-tyrosine kinase inhibitors,” J Med Chem Oct. 1, 1993;36(20):3010-4), piceatannol (3,4,3′,5′-tetrahydroxy trans stilbene, aplant secondary natural product; N. C. Mishra et al., “Inhibitory effectof piceatannol, a protein tyrosine kinase inhibitor, on asexualmaturation of Plasmodium falciparum,” Indian J Exp Biol 1999 April;37(4):418-20; K. Thakkar, “Synthesis and protein-tyrosine kinaseinhibitory activity of polyhydroxylated stilbene analogues ofpiceatannol,” J Med Chem Oct. 1, 1993; 36(20):2950-5), hymenialdisine(SK&F 108752) and herbimycin (A. M. Badger et al., “Inhibition ofinterleukin-1-induced proteoglycan degradation and nitric oxideproduction in bovine articular cartilage/chondrocyte cultures by thenatural product, hymenialdisine,” J Pharmacol Exp Ther 1999 August;290(2):587-93), kaempferol and quercetin (and the kaempferol glycosideskaempferol-O3alpharhamnopyranoside andkaempferol-O3-alpha-arabinopyranoside, M. Abou-Shoer et al., “Flavonoidsfrom Koelreuteria henryi and other sources as protein-tyrosine kinaseinhibitors,” J Nat Prod 1993 June; 56(6):967-9; M. Cushman et al.,“Synthesis and protein-tyrosine kinase inhibitory activities offlavonoid analogues,” J Med Chem 1991 February; 34(2):798-806), anderbstatin and tyrphostins (e.g., M. Treuner et al., “Limited selectivityof a synthetic erbstatin derivative for tyrosine kinase and cell growthinhibition,” Biochem Int 1992 March; 26(4):617-25); a reduced novelbenzofluoranthene, tentatively named as (6bS,7R,8S)-7-methoxy-4, 8,9-trihydroxy-1,6b,7,8-tetrahydro-2H-benzo[j] fluoranthen-3-one (XR774),from Cladosporium cf. cladosporioides (R. Sadeghi et al., “Differentialregulation of CD3- and CD28-induced IL-2 and IFN-gamma production by anovel tyrosine kinase inhibitor XR774 from Cladosporium cf.cladosporioides,” Int Immunopharmacol 2001 January; 1(1):33-48).

[0026] As used in the claims, a “natural” inhibitor of EGFR means acompound, mixture, isolate, extract, or the like having the ability toinhibit the activation of EGFR (e.g., as described below), and which isderived from a substance or organism existing in nature, used as a foodsource (or nutritional supplement) in its existing form or derivedtherefrom, or used as a cosmetic or derived therefrom, and minorchemical modifications of such substances. Soy beans, for example, arenatural substances, and bean curd is a food source derived therefrom;from either the bean or the curd once can isolate or extract genisteinand other isoflavones. Minor chemical modifications to such isolates orextracts are meant those which are relatively simple in nature andanalogous to those modifications presently used for foods andnutritional supplements, for some pharmaceuticals, and for foods. Suchmodifications include, for example, making simple pro-drugs, such asesterification of retinol (usually providing retinyl acetate or retinylpalmitate which convert to retinoic acid in the skin); similarmodification include making salts or esters of ascorbic acid, or makingdifferent salts of zinc (e.g., zinc sulfate or zinc gluconate to deliverzinc orally), or hydrogenation of vegetable oils, and so on. This is notto ascribe or limit the present invention to any particular mechanism ofinhibition, as any given substance that has EGFR inhibitory effects mayinhibit the binding of HB-EGF to the EGFR, the binding of EGF-EGFR toATP, and/or the ability of phosphorylated-EGFR to bind to the substrate(such as an adjacent EGFR). One screening method for determining theability of a given compound to inhibit the activation of EGFR is to usecultured cells or an organ culture, preferably using human cells (suchas the human skin organ culture used in the above-referenced Stoll andElder paper) that have been challenged with an agonist known to induceEGFR activation, such as retinoic acid (or another retinoid). Theability of a compound to exhibit retinoid activity can be determined byexamining the induction of cytoplasmic retininoic acid binding protein(CRABP) or its DNA (as in U.S. Pat. Nos. 5,871,909 and 5,654,137, thedisclosures of which are both incorporated herein by reference) afterchallenge with the test retinoid compound. Although not essential, butdesirable, the test agonist compound can also be used in combinationwith a Western blot to assure that the total amount of EGFR is unchangedand that only the amount of EGFR activated/phosphorylated is increased(as was the case with the experiments shown in FIG. 1). The culturedcells or organ culture are exposed to the desired agonist compound, thenthe test inhibitor compound is added, and finally the cells are examined(such via Western blot) to determine the extent of EGFR activation.

[0027] An EGFR activation inhibitor compatible with a retinoid usedtherapeutically for the treatment of humans via topical application thatcan be admixed into the same composition as the retinoid is provided(assuming it is compatible with the other excipients in that compositionas well). The amount of inhibitor used depends on the selectivity of theinhibitor for the EGFR, whether it is a reversible or irreversibleinhibitor, its ability to penetrate the skin (the composition mayinclude a penetration enhancer), its stability, its metabolism, and thelike. In general, 0.1% to 10%, more preferably about 5% by weight of thecomposition of a reversible inhibitor is used; lesser amounts of anirreversible inhibitor are used. A combination of reversible andirreversible inhibitors can also be used.

[0028] As an alternative to, or in addition to, combining the inhibitorwith the retinoid, a separate composition comprising the inhibitor, anda dermatologically suitable carrier, can be applied by the patient asneeded, and/or concomittantly with the application of the retinoid. Itwould be preferable if the patient started the inhibitor “therapy” aboutsometime prior to starting the retinoid therapy, preferably between onehour and 48 hours prior (depending on the inhibitor used and its mode ofadministration). Preferably, the inhibitor therapy should be continuedfor some time after the retinoid therapy has ended, preferably at leastone day, more preferably for about one week. As different patients canrespond differently, a separate composition is also useful even incombination with a primary composition that is a combination of aretinoid and an inhibitor, as the inhibitor in the primary compositionmay not provide the optimal effect. Further, for a commercial productthat is the retinoid/inhibitor combination, it is likely that therewould be only a limited number of specific retinoid/inhibitor strengths,and so a separate inhibitor composition would be a desirable adjunct inthe not unlikely event that the inhibitor in the retinoid/inhibitorcomposition is not as effective as desired for some patients. For theseparate inhibitor composition, additional beneficial ingredients thatdo not interfere with the retinoid therapy or the action of theinhibitor can be present, and especially those that would help toalleviate retinoid therapy side effects. Such ingredients can includehumectants, moisturizers, emollients, and even mild antibacterials (suchas benzalkonium chloride) and mild anesthetics (such as benzocaine), andcompatible mixtures thereof. Additional ingredients as conventionallyused, including fragrances, colorants, and the like can be present asdesired. The primary retinoid/inhibitor composition, the separateinhibitor composition, or both can be provided as a cream, a gel, alotion, a spray, and in such other forms as are typically formulated inthe dermatological and cosmetics industries.

[0029] The present invention may allow increased dosing (application) ofretinoid in patients requiring increased dosing. Retinoid dosing,depending on the condition being treated, with this invention willtypically range between four times daily and once weekly, although moreor less frequent retinoid application may be desirable depending on thecondition treated and the patient's response. Likewise, application ofthe inhibitor may range from four or more times daily to once or fewertimes each week, again depending on the side effects of the retinoidtreatment experienced by the patient.

[0030] As described herein, it should be understood that all retinoidtherapy, whether via topical or systemic (e.g., oral) administration,induces HB-EGF, which binds to the EGFR, which then activates itself andcauses the side effects that the present invention alleviates. While thein vivo data presented herein used UV light rather than a retinoid asthe agonist, and thus by-passed the HB-EGF mode of activating the EGFR,it should be apparent to the artisan of ordinary skill that the presentinvention provides a method and composition for alleviating any sideeffect caused by EGFR phosphorylation, whether induced by UVirradiation, retinoid therapy for acne, a cancer therapy, and any othermechanism by which the EGFR becomes activated/phosphorylated.Additionally, while treatments in human have been described herein,retinoids and other compounds that activate the EGFR are also used invetinary therapies, and the present methods and compositions wouldalleviate EFGR activation-induced side effects in animals.

[0031] Other situations in which EGFR is likely activated occur withirritant contact dermatitis (ICD) from soaps, detergents, surfactants,and other cleansing and cleaning compositions. People who work in humanor animal health care or in foodstuff preparation must frequently washtheir hands to avoid contamination and cross-contamination. People whowork with or are exposed to various chemicals, from lubricants andgreases, to paints, to lawn and agricultural chemicals, to detergentsand cleaning/degreasing agents, to photographic and printing chemicals,are often exposed to such compositions on a daily or ongoing basis.Chronic exposure of a person's skin to such compositions often resultsin peeling, cracking (eczema craqué), and/or a thickening of the skin.Such symptoms are highly suggestive of activation of the EGFR, resultingin hyperproliferation of skin cells, leading to peeling, cracking, andthickening of the skin. Unlike allergic contact dermatitis (ACD), wherea small amount of the compound functions as an allergen, and thedermatitis is mediated by an immune response (so that a minor futureexposure can result in a dramatic dermatitis), irritant contactdermatitis is typically mediated by a dose-response relationship (thehigher the exposure, the more vigorous the dermatitis reaction). Onemethod for ameliorating these symptoms is to incorporate an EGFRinhibitor into the soap, detergent, surfactant, or other cleansing orcleaning composition used by the person in an amount of between 0.1% and10%, more preferably between 1% and 7% by weight. Preferred EGFRinhibitors are the natural or botanically derived inhibitors discussedabove, especially genistein and quercetin, and especially those that canbe stably incorporated into the cleansing composition. The EGFRinhibitor can be used with a soap (or detergent, etc.) that is in bar orsolid form, or one that is provided as a liquid or lotion (includingshampoo). For example, a health care worker having to wash his handsperhaps ten to 20 times a day and suffering from ICD due to the chronicand intense exposure to soap benefits from a soap having an EGFRinhibitor prophylatically preventing the ICD. Analogously, a landscaperexposed to fertilizers, herbicides, and fungicides, or an auto mechanicexposed to grease and lubricants, and various hydraulic and heatconducting fluids, would benefit from cleaning up using a soap having anEGFR inhibitor. Still further, as animals suffer similar EGFR-inducedICD, an animal shampoo having an EGFR inhibitor would benefit both theanimal and the human shampooer. Of course, the other ingredients in thesoap or cleanser are preferably not EGFR-activating, if not alsohypoallergenic. Such a cleanser preferably would also includemoisturizers, emollients, and the like such as lanolin (not lanolinalcohol).

[0032] As seen, various substances, such as retinoids, and various otherconditions, such as psoriasis or sunburn, can activate the EGFR. Anysubstance or condition that activates the retinoic acid receptor (RAR,including the alpha, beta, and gamma subtypes), or any substance that isconverted into a compound that activates RAR, can trigger EGFR,resulting in hyperproliferation and peeling. For example, a retinylester applied topically is converted to a substance that activates RARin the outer epidermis. In turn, HB-EFG is produced, which goes to thebottom layer of the epidermis and, as described above, activates theEGFR. Thus, inhibitors of the MAPK (MAPKK, MAPKKK), ERK,phosphorylated-JUN, and the like are useful for preventing activation ofthe EGFR.

[0033] Any substance (such as a retinoid) or condition (skin damage)that acts as a stimulus for growth of the skin can hyperproliferationand thereby cause peeling, to the extent that the growth is caused bythe activation of the epidermal growth factor. Thus, as explained above,perceived injury to the skin due to detergents can cause the skin toproliferate, resulting in peeling, even though from a layman's point ofview there should not be any injury to the skin from merely washing withsoap.

[0034] The foregoing description is meant to be illustrative and notlimiting. Various changes, modifications, and additions may becomeapparent to the skilled artisan upon a perusal of this specification,and such are meant to be within the scope and spirit of the invention asdefined by the claims.

What is claimed is:
 1. A cleansing composition for a human or other landanimal, comprising: A. a cleanser selected from the goup consisting ofsoaps, surfactants, detergents, and mixtures thereof; and B. aneffective amount of a natural EGFR inhibitor.
 2. The cleanser of claim1, wherein the EGFR inhibitor is present in an amount between 0.1% and10% by weight.
 3. The cleanser of claim 2, wherein the EGFR inhibitor ispresent in an amount between 1% and 7% by weight.
 4. The cleanser ofclaim 1, wherein the inhibitor is selected from the group consisting ofgenistein, quercetin, equol, indolecarbazole, staurosporine,lavendustin, daidzein, and erbstatin, and mixtures thereof.
 5. Thecleanser of claim 4, wherein the inhibitor is selected from the groupconsisting of genistein, quercetin, equol, and mixtures thereof.
 6. Thecleanser of claim 4, wherein the inhibitor is provided as a ground orpowdered soy (soya) product, including soy bean.
 7. The cleanser ofclaim 1, wherein the cleanser is a cleanser for use on animals.
 8. Acomposition for dermatitis presenting as hyperproliferation of skincells on the hands caused by activation of the EGF, comprising a naturalinhibitor of EGFR and a dermatologically suitable carrier therefor. 9.The composition of claim 8, wherein the inhibitor is an isoflavone. 10.The composition of claim 8, wherein the inhibitor is selected from thegroup consisting of genistein, quercetin, equol, indolecarbazolestaurosporine, lavendustin, daidzein, and erbstatin, and mixturesthereof.
 11. The composition of claim 10, wherein the inhibitor isgenistein and is derived from a soy product.
 12. The composition ofclaim 10, wherein the inhibitor is genistein or quercetin or both.
 13. Amethod for for alleviating dermatitis presenting as hyperproliferationof skin cells on the hands, comprising: administering to the skin of anaffected person's hand an amount of a natural inhibitor of EGFReffective to decrease EGFR activity, said EGFR inhibitor administeredtopically in a dermatologically suitable carrier.
 14. The method ofclaim 13, wherein the hyperproliferation is due to chemical contact onthe hand.
 15. The method of claim 14, wherein the hyperproliferation isdue to the use of a cleanser.
 16. The method of claim 13, wherein theinhibitor is an isoflavone.
 17. The method of claim 13, wherein theinhibitor is selected from the group consisting of genistein, quercetin,equol, indolecarbazole staurosporine, lavendustin, daidzein, anderbstatin, and mixtures thereof.
 18. The method of claim 13, wherein theinhibitor is genistein or quercetin.
 19. The method of claim 18, whereinthe inhibitor is genistein and is derived from a soy product.